en
Scientific article
English

Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2

Published inMolecular Cell, vol. 58, no. 6, p. 977-988
Publication date2015
Abstract

Target of Rapamycin (TOR) plays central roles in the regulation of eukaryote growth as the hub of two essential multiprotein complexes: TORC1, which is rapamycin-sensitive, and the lesser characterized TORC2, which is not. TORC2 is a key regulator of lipid biosynthesis and Akt-mediated survival signaling. In spite of its importance, its structure and the molecular basis of its rapamycin insensitivity are unknown. Using crosslinking-mass spectrometry and electron microscopy, we determined the architecture of TORC2. TORC2 displays a rhomboid shape with pseudo-2-fold symmetry and a prominent central cavity. Our data indicate that the C-terminal part of Avo3, a subunit unique to TORC2, is close to the FKBP12-rapamycin-binding domain of Tor2. Removal of this sequence generated a FKBP12-rapamycin-sensitive TORC2 variant, which provides a powerful tool for deciphering TORC2 function in vivo. Using this variant, we demonstrate a role for TORC2 in G2/M cell-cycle progression.

Keywords
  • Antifungal Agents/metabolism/pharmacology
  • Binding Sites/genetics
  • Biocatalysis/drug effects
  • Blotting
  • Western
  • Carrier Proteins/chemistry/genetics/metabolism
  • Cell Cycle/drug effects/genetics
  • Cell Cycle Proteins/chemistry/genetics/metabolism
  • Drug Resistance/genetics
  • Mass Spectrometry/methods
  • Mechanistic Target of Rapamycin Complex 2
  • Microscopy
  • Electron
  • Multiprotein Complexes/chemistry/genetics/metabolism
  • Mutation
  • Phosphatidylinositol 3-Kinases/chemistry/genetics/metabolism
  • Protein Structure
  • Tertiary
  • Saccharomyces cerevisiae/drug effects/genetics/metabolism
  • Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism/ultrastructure
  • Sirolimus/metabolism/pharmacology
  • TOR Serine-Threonine Kinases/chemistry/genetics/metabolism
Research group
Citation (ISO format)
GAUBITZ, Christl et al. Molecular Basis of the Rapamycin Insensitivity of Target Of Rapamycin Complex 2. In: Molecular Cell, 2015, vol. 58, n° 6, p. 977–988. doi: 10.1016/j.molcel.2015.04.031
Main files (1)
Article (Published version)
accessLevelRestricted
Identifiers
ISSN of the journal1097-2765
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